Abstract for CHARGE Admin Supplement to study Down Syndrome. This application is being submitted to PA-18-591 in accordance with NOT-OD-18-194. This proposed Administrative Supplement will add several research questions related to Down Syndrome (DS), utilizing a subset of children who have been participating in the CHARGE Study (CHildhood Autism Risks from Genes and Environment, R01-ES015359, PI: Hertz-Picciotto), beginning in 2003. The CHARGE Study has enrolled about 2000 children with autism spectrum disorder (ASD); children with developmental delays but not symptoms of ASD (DD, of which over 30% have Down Syndrome(DS)/Trisomy 21); and children with typical development (TD). All three groups were identified from a population-based sampling frame. To date, 92 DS children have been enrolled. In this project, biologic specimens and data on maternal and child health will be utilized to understand pathophysiology of DS from epigenetic, metabolomic and environmental perspectives. For each research question, DS children will be compared with those from three other groups: idiopathic DD, TD, and ASD. Broadly, this research will address: 1) how does the blood metabolome in DS differ from the metabolomes of children in each of the three comparison groups? 2) in which regions of the genome do newborns with DS differ from the other groups with regard to their newborn bloodspot DNA-methylation? 3) do environmental stressors (pesticides, maternal diabetes and economic hardship) alter the risk, severity of cognitive impairments, and comorbidities of sleep disturbances and seizure disorders among children with DS? Additionally, the relationships between these three stressors and the metabolomic and epigenetic biomarkers will be examined. Overall, this project will capitalize upon a large cohort of children with different developmental status for whom the CHARGE Study has already collected a broad range of phenotypic information and biological specimens in order to elucidate molecular mechanisms and pathways that contribute to the pathologies in a range of organ systems that characterize DS. Results will bring us closer to identification of targets for therapeutic interventions designed to improve the functioning, health and well-being of individuals with DS.